Acute alcohol intoxication is clearly a risk for sustaining traumatic injury. Our recently completed epidemiologic study of trauma patients demonstrated that having a positive blood alcohol content is an independent risk factor for developing acute lung injury (ALI) in the first five days of hospitalization (Odds Ratio 1.40; 95% Confidence Interval 1.22-1.60; p< 0.0001). Our pilot study of ex vivo blood lymphocyte activation in human subjects that consumed alcohol to simulate binge drinking showed substantially increased PHA-induced interferon (IFN)-? and interleukin (IL)-2 secretion 20 minutes after alcohol ingestion and lasting for up to 5 hours. Our goal is to elucidate the mechanism by which acute alcohol intoxication increases the risk of organ injury in trauma patients. Our central hypothesis is that acute alcohol exposure potentiates leukocyte activation by increasing intracellular reactive oxygen intermediate (ROI) production, which amplifies expression of proinflammatory cytokines that can cause injury to tissues including lung. The following Specific Aims have been developed to address this hypothesis while providing me with valuable new research skills in basic and translational research techniques that will complement my previous training in clinical and epidemiologic investigation. We will test our hypothesis using a human alcohol binge-drinking model. Specifically we will (1) determine how acute alcohol ingestion modifies lymphocyte, monocyte, and neutrophil response to ex vivo activation and the potential role of intracellular ROI in mediating these effects; and (2) analyze how acute alcohol ingestion modifies cytokine expression, leukocyte activation, and ROI generation in response to intravenous endotoxin LPS infusion in normal human subjects. We anticipate that the proposed studies will increase our understanding of how alcohol intoxication can modify host response to increase risk of lung and other organ injury, determine if and how a follow-up Phase II Clinical Trial of antioxidants in intoxicated trauma patients should be conducted, provide me with an excellent framework on which to expand my translational research skills, and produce publications that will propel my career as a pulmonary and critical care physician scientist and translational investigator.